The ability to perceive and orient to new information is crucial to survival. The centre median and parafascicular nuclei (CM/Pf) of the thalamus are hypothesized to play a critical role in the sensorimotor process of attentional orienting. Recent studies have suggested that information about salient sensory input is relayed through CM/Pf to forebrain targets, where it serves to interrupt ongoing processing and redirect attention to the salient stimulus. The proposed research will test this hypothesis by assessing the specific impact of sensory processing in CM/Pf on its downstream targets in neocortex and basal ganglia using a combination of correlative, causal (optogenetic) and behavioral measures. In the mouse, lateral and medial Pf are homologous to the CM (sensorimotor) and Pf (associative) thalamic nuclei of primates, respectively. We will systematically test the impact of mouse lateral Pf activity on stimulus representations in primary somatosensory neocortex (SI) and dorsolateral (sensorimotor) striatum (DLS) using a 2-vibrissa stimulation paradigm in which the salience of each stimulus is manipulated according to its probability of occurrence. In Aim I, in vivo extracellular recordings will be performed using genetically modified mouse lines that enable us to specifically identify rare subtypes of neurons in SI and DLS onto which Pf projections are known to synapse. In Aims II and III, an optogenetic approach will be used to transduce the projection neurons in lateral Pf with light-activated membrane proteins that allow temporally precise stimulation or silencing of these neurons. Using lightly anesthetized mice in Aim II, extracellular recording in SI and DLS will be combined with optical stimulation in Pf on a subset of trials, providing causal testing of the impact of Pf firing on downstream stimulus representations for both low-probability (salient) and high-probability (non- salient) stimuli. In Aim IIIB, similar experiments performed in awake mice during the head-fixed detection task will test the impact of Pf during behaviorally relevant stimulus detection. By testing the impact of Pf on salience representations in SI and DLS, the proposed studies will critically examine the widely hypothesized role of Pf in attentional orienting. PUBLIC HEALTH RELEVANCE: Deep brain stimulation in the centre median and parafascicular nuclei of the thalamus has been shown to alleviate symptoms in a diverse array of neurological diseases and disorders. These include epilepsy and minimally conscious states, as well as central pain and Parkinson's disease, highlighting the importance of these nuclei in healthy brain dynamics in general and sensorimotor functions in particular. The proposed research will investigate the impact of sensory processing in the centre median and parafascicular nuclei on downstream sensory representations in neocortex and basal ganglia targets.